The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Linagliptin i.e. 8-[(R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methyl-quinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione of Formula (1) or salts thereof is disclosed in U.S. Pat. No. 7,407,955 B2 and the process by which it can be prepared.

U.S. Pat. No. 7,820,815 B2 discloses an alternative process for preparing linagliptin using (R)-3-phthalimidopiperidine tartrate as an intermediate.
U.S. Patent Application Publication No. 2007/0259900 A1 (the US '900 A1) discloses five crystalline forms of linagliptin namely Form-A, Form-B, Form-C, Form-D and Form-E. The US '900 A1 also discloses that the compound prepared in WO 2004/018468 A2 is present at ambient temperature as a mixture of two enantiotropic polymorphs. The temperature at which the two polymorphs transform into one another is 25±15° C.
The US '900 A1 discloses that pure high temperature form (polymorph A) can be obtained by heating the mixture to temperatures >40° C. and its melts at 206±3° C. and is characterized by x-ray powder diagram and d-values. Further US '900 A1 also discloses that the low temperature (polymorph B) is obtained by cooling to temperatures <10° C.
According to the European Medicines Agency Assessment Report for Trajenta (linagliptin), the active substance is a white to yellowish crystalline solid substance and simultaneously exists in two polymorphic forms, which are enantiotropically related and which reversibly convert into each other approximately at room temperature. The two polymorphic forms do not differ with regard to biopharmaceutical properties.
IP.COM Journal Vol. 12 (4A) Pg. 15 (2011) i.e. IPCOM000210079D discloses a process for preparing an amorphous form of 8-[(R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methyl-quinazolin-2-yl)methyl]xanthine i.e. linagliptin by dissolving linagliptin in dichloromethane and evaporating under reduced pressure to afford dry solid residue which was amorphous by XRD. This process has the drawback of removal of residual solvent. The dichloromethane is difficult to remove from amorphous linagliptin even upon prolonged drying.
Another example provided discloses a process for preparing an amorphous form of linagliptin by mixing linagliptin in ethanol to get partial dissolution followed by evaporation under reduced pressure to obtain dry solid residue. This solid residue was reported to be amorphous. The said process may not be suitable for industrial application as the residue obtained has higher amount of residual ethanol.
IP.COM Journal Vol. 12 (4A) Pg. 15 (2012) i.e. IPCOM000216218D published after the priority date of this application discloses process for preparation of amorphous 8-[(R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methyl-quinazolin-2-yl)methyl]xanthine hydrochloride i.e. linagliptin hydrochloride which is cited herein as reference.
The processes disclosed in the prior art doesn't provide amorphous linagliptin which is suitable in use for pharmaceutical developments. The prior art provides amorphous linagliptin which is having higher amount of residual solvents and the processes not applicable for commercial manufacturing.
U.S. Patent Application Publication No. 2010/0209506 A1 discloses a pharmaceutical composition comprising linagliptin as a first active pharmaceutical ingredient and a glucopyranosyl-substituted benzene derivative as second active pharmaceutical ingredient wherein the linagliptin has a particle size distribution of d90<200 μm.
Therefore, there is a need to provide a process for the preparation of amorphous linagliptin which is substantially free from residual solvent and the processes are industrially scalable for bulk manufacturing. Further, the process provides an amorphous form of linagliptin which is at least stable at ordinary storage conditions during stability.
Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavailability pattern may be favoured over another.
An amorphous form of some of the drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may result in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.
In view of the above, it is therefore, desirable to provide an efficient, economical and eco-friendly process for the preparation of stable amorphous form of linagliptin.